Fatty alcohol-propylene glycol vehicle

ABSTRACT

A substantially non-aqueous medicant vehicle containing from 15 to 45 parts saturated fatty alcohol having from 16 to 24 carbons, from 45 to 85 parts glycol solvent, from 0 to 15 parts plasticizer, from 0 to 15 parts coupling agent, 0 to 20 parts penetrant, and if desired, other pharmaceutical adjuvants. This base is a suitable vehicle for all types of therapeutic agents for topical application including antibiotics, steroids, antihistamines, antiseptics, anesthetics, antibacterials, fungicides, and the like. The vehicle has shown particular advantages with anti-inflammatory topical corticoids.

United States Patent 1 1 1111 3,888,995 Katz et al. *June 10, 1975 [541FATTY ALCOHOL-PROPYLENE GLYCOL 3,342,676 9/1967 Szabo et al. 424/358 xVEHICLE 3,352,753 11/1967 Lerner 424 241 3,472,931 /1969 Stoughton....424/240 X [751 lnvemors- Afhemnncahh 3,482,018 12/1969 Szabo et al.424/358 x Berber Ph1l3de1lh1a1 3,551,554 12/1970 Herschler 424/7 Pa.3,592,930 7/1971 Katz et al 424/243 [73] Assignee: Syntex Corporation,Panama FOREIGN PATENTS 0R APPLICATIONS Notice: The portion of the termof this 4971263 12/938 United Kingdom patent subsequent to July 13,1988, g

ermany has been d1scla1med. 1,080,735 4/1960 Germany [22] Filed: Mar. 3,1971 2 1 App]. No: 120 91 Primary Examinershep K. Rose Attorney, Agent,or FirmJoseph l. Hirsch; William B. Related U.S. Application Data walker[62] Division of Scr. No. 745,989, July 19, 1968, Pat. No.

3592930 57 ABSTRACT [52] U.S. Cl 424/358; 424/243 A substantiallynon-aqueous medicant vehicle contain- [51] Int. Cl N6lk 9/06 ing from 15to parts saturated fatty alcohol having [58] Field of Search 424/358from 16 to 24 carbons, from 45 to parts glycol solvent, from O to 15parts plasticizer, from 0 to 15 parts [56] References Cited couplingagent, 0 to 20 parts penetrant, and if desired, UNITED STATES PATENTSother pharmaceutical adjuvants. This base is a suitable 2 857 7,1939Jacobowitz 474/358 X vehicle for all types of therapeutic agents fortopical 2600344 6/1952 Van iii f""""II J' application includingantibiotics, steroids, antihista- 2:779:707 1 1957 Jacobson et al.424/240 mines, antiseptic-S, anesthetics, antibacterials. f 2,84l,5277/1958 Freedman et al 424/24 cides, and the like. The vehicle has shownparticular 2,856.329 10/1958 Taylor et al. 424/240 advantages withanti-inflammatory topical corticoids. 3,071,5ll l/l963 Sasaki et al424/243 3,210,248 10/1965 Feldmann et al. 424/239 11 Clams, N0 DrawmgsFATTY ALCOHOL-PROPYLENE GLYCO VEHICLE This application is a division ofapplication Ser. No. 745,989, filed July 19, 1968. now U.S. Pat. No.3,592,930 issued July 13, 1971.

This invention relates to vehicles for topical applications of medicants(i.e., active ingredients) and to mixtures of the vehicles andmedicants. In particular, this invention relates to new, improvedmedicant vehicles having advantages over previously known vehicles.

One of the oldest types of medicant vehicles is the ointment, apreparation containing active medications that can be readily spread onand rubbed into the skin. It serves as a means for distributing themedication uniformly over the skin surface and maintaining it thereuntil beneficial action can occur. The earliest preparations were basedon fats, greases and petrolatum. These are, by nature, greasy, are notwater-washable and have a limited ability to release medication to theskin. A non-aqueous ointment of more recent origin is Carbowax, agrease-like mixture of polyethylene glycols (molecular weight of 1000 to20,000). This vehicle, although water-washable, has a greasy texture anddoes not provide an occlusive coating on a treated surface. Prior tothis invention, these anhydrous ointment bases were the only vehiclesavailable for medicants which deteriorate in the presence of moisture.

Emulsified creams, such as cold creams, were developed to reducegreasiness, while still maintaining the unctuousness and spreadabilityof the older grease-type ointments. The emulsified creams have anaqueous base, however, and are not suitable as vehicles for many drugsbecause their pH or water content may destroy the medicant. Themedicant, in turn may destroy the emulsions, that is, break theemulsions and permit separation of the vehicle components. Theseemulsions also must contain surfactants as emulsifiers and wettingagents.

It is accordingly the purpose of this invention to provide anessentially anhydrous, water-washable base which is more effective thanstandard anhydrous ointment bases of the grease-typebecause it canpreserve the activity of medicants which deteriorate in the presence ofmoisture; provide an occlusive film for longer and better therapeuticactivity; release the medicants more quickly and effectively; bringdissolved antibacterial agents in known dilution in contact with theskin; spread evenly and adhere well even if the skin is moist; be easilyremoved with water from skin or fabrics; be soluble in water and thuspermit the incorporation of aqueous ingredients; provide media toreadily absorb discharges from wounds; serve as an excellent levigatingmaterial for many prescribed ingredients that usually require separatetreatment before being incorporated into ointment bases; and because itdoes not hydrolyze, deteriorate, become rancid, or support mold growth.I

The medicant vehicle or base according to this invention can have thecomposition shown in Table A.

Table A-Continued Concentration Weight percent or parts by weight perparts.

All concentrations are herein given as weight percents or parts byweight unless otherwise specified. lt is also intended that the chemicalcompounds in each class of ingredients discussed hereinafter be limitedto pharmaceutically acceptable compounds in the concentrationsindicated.

The fatty alcohol ingredient in the vehicle composition of thisinvention can be any saturated fatty alcohol having from 16 to 24carbons or mixtures thereof, and is preferably a monohydric primaryalcohol. Suitable fatty alcohols'include cetyl alcohol, stearyl alcohol,behenyl alcohol, and the like. Vehicles having excellent properties havebeen made using stearyl alcohol, or mixtures of cetyl, stearyl andbehenyl alcohols as the fatty alcohol component. The fatty alcoholcomponent must be substantially free from any significant amount ofunsaturated alcohols or fatty alcohols having fewer than lo carbons. Theterms substantially free from", as used herein, is defined as indicatingthe compositions of this invention contain less than irritating orotherwise medically undesirable amounts of the indicated substances.Since the C to C fatty alcohols available commercially containimpurities including some proportion of fatty alcohols having fewer than16 carbons, total avoidance of alcohols having fewer than 16 carbonsfrom the mixture is not practicable. Careful selection of raw materialsis preferable, however, to maintain the percentage of irritating fattyalcohols to less than 10 percent of the total fatty alcoholconcentration.

The glycol solvent component can be a propylene glycol such as '1,2-propylenediol, 1,3-propylenediol, polyethylene glycol having amolecular weight of from 100 to 800, dipropylene glycol, etc., andmixtures thereof. I

The fatty alcohol and glycol solvent ingredients are the principlecomponents and are satisfactory as the sole vehicle components in thecomposition of this invention. The glycol solvent can function either asa solvent for a glycol-soluble medicant or a carrier for aglycol-insoluble medicant. The fluidity of the composition increaseswith increased concentrations of the glycol solvent. In the combinationwith the glycol solvent, the fatty alcohol (a solid component whichnaturally thickens the composition) forms a unique protective, lubricantand occlusive film which is highly desirable in several types ofdermatological preparations.

The composition can also contain a compatible plasticizer such aspolyethylene glycol having a molecular weight of from above 800 to20,000, 1,2,6-hexanetriol, sorbitol, glycerol, and the like. Theplasticizer maintains homogeneity in the fatty alcohol-glycol solventmixture at ambient temperatures, that is, temperatures at which thefatty alcohol is naturally a solid. This component also improves theplasticity and uniformity of medicant mixtures with the vehicle andprovides to the vehicle smoothness and a more pleasing" feel; hence thevehicle containing the plasticizer is more pharmacologically acceptable.

The term compatible is defined herein to indicate a component which willnot cause separation (loss of homogeneity) of the other components, thatis, the fatty alcohol and glycol solvent at temperatures up to 45C.

The plasticizer concentration can be within the range of from topercent. Concentrations above 15 percent may provide a composition whichhas a consistency unsuitable for normal applications or causeinstability of the vehicle mixture and some separation of thecomponents. In general, the particular plasticizer concentrationnecessary to provide a desired consistency, degree of smoothness andplasticity will vary with the choice of the fatty alcohol component, thechoice of glycol solvent, and the ratio of these components in thevehicle.

The particular concentration of plasticizer which will provide the moststable composition will depend upon the choice of plasticizer, andchoice and concentration of the other ingredients. Preferably, theplasticizer concentration should be balanced so the vehicle hasfreeze-thaw stability, i.e does not separate after repeated cycles ofsolidification (by cooling) and liquefaction (by heating).

The vehicle of this invention can also contain a compatible,pharmaceutically acceptable coupling agent, the term compatible havingthe above-defined meaning. Suitable coupling agents include saturatedfatty acids having from 16 to 24 carbons such as stearic acid, palmiticacid, behenic acid; fatty amides such as oleamide, palmitamide,stearamide, behenamide; and esters of fatty acids having from 16 to 24carbons such as sorbitan monostearate, polyethylene glycol monostearate,propylene glycol monostearate and the corre sponding mono-esters ofother fatty acids such as oleic acid and palmitic acid. Best coupling isachieved, particularly with the esters, if the fatty group of thecoupling agent and fatty alcohol is the same or has approximately thesame number of carbons. It is essential that the fatty acids besaturated and the fatty acids and amides be essentially free fromirritating amounts of acids or amides having fewer than 16 carbons.

The coupling agent concentration can be within the range of from 0 to 10percent. In general, the coupling agents maintain homogeneity of thevehicle and prevent exudation or bleeding of the more liquid componentsof the vehicle (glycol solvent) upon prolonged storage at elevatedtemperatures. The medicant vehicle preferably contains a quantity of thecoupling agent sufficient to prevent visible exudation of the glycolsolvent from the vehicle after storage at 45C for 48 hours. No more ofthe coupling agent is required than is needed to prevent this exudation.Excess quantities are undesirable because other ingredients and theirfunctions are needlessly diluted. If the coupling agent concentration isnot carefully balanced with the other components, stability of themedicant vehicle after one or more repeated cycles of solidification (bycooling) and liquefaction (by heating), that is, the freeze-thawstability is impaired.

The penetrants increase the penetration and therapeutic activity of themedicants and are usually solvents or co-solvents for the medicants. Thepenetrants can be used in concentrations which are pharmaceuticallyacceptable for the intended use not to exceed percent of the weight ofthe vehicle. Representative examples of penetr 118 includedimethylsulfoxide, dimethylacetamide, dimethylformamide, and the like.

It should be understood that the medicant vehicles of this invention canalso contain non-essential ingredients. The vehicle can contain up to 10weight percent of conventional pharmaceutical adjuvants. These adjuvantsor additives are conventionally used to improve consistency,homogeneity, spreadability, texture and appearance of the vehicle or itsresidual film. They can be used to give to a residual film, varyingdegrees of continuity, flexibility, adhesion, occlusion, waterrepellancy, washability, and the like. Examples of typical adjuvantsinclude surfactants (cationic, anionic, or nonionic) such as Pluronics,polyoxyethylene-polyoxypropylene copolymers; gums such as natural gumsincluding agar, acacia gum, guar gum, tragacanth, and the like;cellulose derivatives including cellulose ethers such as methylcellulose, ethyl cellulose, carboxymethyl cellulose, and the like;starch and starch derivatives; and water-soluble vinyl polymers such aspolyvinylpyrrolidone, polyvinyl alcohol, vinylpyrrolidonevinyl alcoholcopolymers, and the like.

The vehicle base of this invention does not contain any significantquantity of petrolatum or mineral oil. It is therefore not a classicalointment and is not waterinsoluble.

The medicant vehicle of this invention is essentially a non-aqueousbase, that is, it is not an emulsion and consequently is not a cream" inthe technical sense. It is preferably anhydrous, but can contain minoramounts of water such as up to 3 percent water. The water concentrationshould not be sufficient to cause separation of the other vehiclecomponents or precipitant medicants dissolved in the vehicle.

The vehicle of this invention can be made from the above ingredients bythroughly mixing them at ambient or elevated temperatures. Preferablythe components are thoroughly mixed while each is in a liquid state, andthe mixture is cooled with good agitation to room temperature. By way ofreferring to a preferred composition as an example, cetyl alcohol,stearyl alcohol, behenyl alcohol, stearic acid, polyethylene glycol and1,2,6- hexanetriol can be mixed with stirring to about -85C; propyleneglycol can be heated to -95C with stirring (a medicant stable at thistemperature could be added to either phase during this step); and thetwo liquids can be mixed with stirring. Good agitation is provided untilthe mixture cools to room temperature.

If desired, additional mechanical agitation and/or shock cooling stepscan be used as intermediate or final steps in the manufacturing processto impart more homogeneity or improve textuure. Processing equipmentsuitable for these steps is known and includes heat exchangers,propeller mixers, colloid mills, homogenizers, roller mills, and thelike.

The base of this invention can be used successfully as a vehicle formost types of therapeutic agents for topical application includingantibiotics such as oxytetracycline, chlortetracycline, streptomycin,bacitracin, chloramphenicol, tyrothricin and the like; steroids havinganti-inflammatory or other beneficial activity; antihistamines such asprophenpyridamine maleate and diphenhydramine hydrochloride; anestheticssuch as benzocaine and lidocaine; antibacterials including iodine,nitrofurazone, sulfanilamide and derivatives, and benzalkonium chloride;fungicides such as undecylenic acid; and older therapeutic agentsincluding coal tar, balsam Peru, ammoniated mercury, chrysarobin,ichthammol, sulfur, and the like.

In corporation of the medicament in this base requires no deviation fromstandard techniques such as those described in Remingtons Practice ofPharmacy, 12th edition by Martin and Cook, Mack Publishing Company 1961A bulky, insoluble powder should be mixed beforehand with a smallproportion of the base mixture or propylene glycol and then blended withthe remainder of the base. These products are usually improved bypassing them through an ointment or roller mill. Many substancesinsoluble in conventional greasy bases will dissolve in thewater-soluble propylene glycol ointment base to give completelyhomogeneous ointments. It may be desirable at times to add the medicinalas an alcoholic or aqueous solution, and these are readily miscible withthe water-soluble bases. Coal tar, ichthammol, balsam Peru and othersthat require special processing in greasy bases can be readilyincorporated in the base of this invention. The medicant can beincorporated into the final base or introduced into the base mixturewith one of its components.

Medicants which are insoluble in propylene glycol can be dissolved orsuspended in the melted fatty alcohol composition. Heat sensitivemedicants (in particular some antibiotics) can be dissolved or suspendedin a small amount of glycol solvent or other liquid, and then mixed withthe vehicle during or after its preparation.

The amount of medicant to be incorporated into the base will, of course,depend upon the type of medicant and its intended use; the determinationof suitable medicant concentrations is a routine matter fully within theconventional skills of the art. In general, therapeutically effectiveamounts of the medicant are incorporated into the vehicle.

The vehicle of this invention is particularly suitable for use withanti-inflammatory topical steroids represented by Formulas I, II andIll.

esters thereof, or when taken together with R ..o /R6 0 R wherein R ishydrogen or alkyl of up to eight carbons, and

R, is hydrogen, or alkyl or an aryl group of up to eight carbons;

R is hydroxy, conventional hydrolyzable esters thereof,tetrahydropyranyloxy, tetrahydrofuranyloxy,4-(lower)alkoxytetrahydropyran-4-yloxy, lower alkoxy, lower cycloalkoxy,lower cycloalkenyloxy, chloro, or fluoro;

R and R are hydrogen, methyl, phenyl, chlorophenyl, fluorophenyl,methylphenyl, or methoxyphenyl (the substituted phenyls preferably beingsubstituted in the para position);

R and R each is hydrogen, chloro, or fluoro;

Z and Z each is a single bond, double bond, or

The terms (lower)alkyl and derivations thereof appearing in the abovedefinitions and elsewhere in the instant specification denote alkylgroups having from one to six carbon atoms, inclusive, such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, amyl, hexyl,and the like.

The term conventional hydrolyzable ester as used herein denotes thosehydrolyzable ester groups conventionally employed in the steroid art,preferably those derived from hydrocarbon carboxylic acids or phosphoricacids and their salts. The term hydrocarbon carboxylic acid defines bothsubstituted and unsubstituted hydrocarbon carboxylic acids. These acidscan be R is hydrogen, methyl, fluoro, or chloro and when Z is a singlebond, R, can be either a or ,8 oriented;

R is hydrogen, chloro, or fluoro; R is keto or T wherein R is hydrogen,hydroxy, chloro, or fluoro;

R is hydrogen, methyl, hydroxy, or conventional hydrolyzable estersthereof;

R is hydrogen, hydroxy, conventional hydrolyzable saturation (includingaromatic), can be of straight chain, branched chain, or cyclicstructure, and preferably contain from one to 12 carbon atoms. Inaddition, they can be substituted by functional groups, for example,hydroxy, alkoxy containing up to six carbon atoms, acyloxy containing upto 12 carbon atoms, nitro, amino, halogeno, and the like, attached tothe hydrocarbon backbone chain. Typical conventional hydrolyzable estersthus included within the scope of the term and the instant invention areacetate, propionate,

hemisuccinate, hemiadipate, hcmi-B,B- dimethylglutarate, acetoxyacetate,2-chloro-4- nitrobenzoate, aminoacetate, diethylaminoacetate,

piperidinoacetate, B-chloropropionate, trichloroacetate,B-chlorobutyrate, dihydrogcn phosphate, dibenzyl phosphate, benzylhydrogen phosphate, sodium bcnzyl phosphate, cyclohexylammonium benzylphosphate, sodium phenyl phosphate, sodium ethyl phosphate,dip-nitrobenzyl phosphate, sodium o-methoxyphenyl phosphate,cyclohexylammonium p-cyanobenzyl phosphate, sodium phenacyl phosphate,benzyl o-carbomethoxyphenyl phosphate, and the like.

By the term aryl are included aryl, aralkyl, and alkaryl groups, such asphenyl, p-chlorophenyl, pmethoxyphenyl, benzyl, phenethyl, tolyl,ethylphenyl, and the like. The wavy line (ll designates and includesboth the alpha and beta configurations.

The above anti-inflammatory steroids have been previously disclosed inUS. Pats. Nos. 3,365,446, 3,067,194, 3,364,203 and 3,053,838 forexample.

The 4'-(lower)alkoxytetrahydropyran-4-yl are prepared from thecorresponding hydroxy compounds by reacting the latter compounds undersubstantially anhydrous conditions with an excess of 4'-(lower)alkoxy-5',6-dihydro-2H-pyran. The reaction is conducted in the presence of asmall amount of an acidic catalyst, such as hydrochloric acid,p-toluene-sulfonic acid, boron trifluoride etherate, and the like,either alone or together with an inert, organic solvent, such asbenzene, diethyl ether, or the like, at a temperature ranging from abutC to about 80C for about five minutes to about 48 hours, thus giving thecorresponding 21- (4-loweralkoxytetrahydropyran-4-yloxy) ethers asexplained more fully in US. Pat. application Ser. No. 731,299 filed May22, 1968.

Prior to the above reaction, protection should be provided for readilyetherified hydroxyl groups other than the C-2l hydroxyl groups, e.g.16a-hydroxy group. Such a group should be selectively acylated such asby reaction with acetic anhydride in pyridine, the quantity of aceticanhydride being sufficient to acylate both the C-l6 and C-21 hydroxylgroups. Hydrolysis of the diacetate in methanol with less than one molarequivalent of sodium carbonate in water yields the l6-acetoxy-2 1-hydroxy product which can be separated by conventional chromatography onneutral alumina, for example. After the above etherification, theacetoxy protecting groups can be removed by treatment of the ester in amethanol solution of potassium hydroxide.

The above anti-inflammatory topical medicants are thoroughly mixed withthe base in therapeutically effective amounts. The particularconcentration of the medicant in the base will vary depending upon theparticular activity of the steroid used considered in con junction withthe condition and subject to be treated.

. In general, therapeutically effective amounts of these compounds canbe as low as 0.00001 weight percent or lower, for example. For someuses, as high as weight percent steroid or higher may be desired.

The medicant base of this invention has been found to be unexpectedlysuperior to previously known vehicles for use with known topicalcorticoids, for example, fluocinolone acetonide (6a,9a-difluoro-l 1B,21-dihydroxy-16a,l7a-isopropylidenedioxypregna-1,4- dicne-3,20-dione) andthe corresponding 2 l-acetate (6a,9a-difluoro-l lB-hydroxyl 60:, 17aisopropylidenedioxy-Z l -acetoxypregna-l ,4-diene- 3,20-dionc). Inpreliminary tests, these medicants have been observed to have severaltimes greater activity in comparision to their activity in previouslyknown vehicles at the same concentration.

This invention is further illustrated by the following specific butnon-limiting examples.

EXAMPLE 1 The following ingredients were mixed at 90C and cooled to roomtemperature with good agitation.

Concentration, wt.%

Formula A B C Ingredients Cetyl alcohol 7.35 9.50 12.60 Stearyl alcohol6.30 8.00 9.45 Behenyl alcohol 1 L55 l2.00 l3.65 Propylene glycol 74.8070.50 64.30

These compositions were found to have the spreadability, penetrabilityand solvent powder required for use with medicants such as steroids,anesthetics, antiseptics, antibiotics, and the like.

EXAMPLE 2 The compositions of Example 1 were found to have greaterplasticity and uniformity when mixed with polyethylene glycol and/orhexanetriol to provide the following formulas.

The addition of saturated fatty acids and/or fatty amides having atleast 16 carbons to the ingredients of Formula D was found to provide avehicle having improved storage characteristics at elevatedtemperatures. In preparing each of the following formulas, theingredients with the exception of propylene glycol were mixed withstirring at 85C, and were then mixed with propylene glycol having atemperature of 95C. The mixture was permitted to cool to roomtemperature with good agitation.

Bacteria ATCC No. Concentration, wt.71 Formula E F Pseudomonasaeruginosa 10145 Protcus vulgaris 88] Staphylococcus aureus 6538 wBacillus cereus 1 1778 Cetyl alcohol 1.75 1.75 Stearyl alcohol 3.50 7.00M ld Behenyl alcohol 12.25 9.75

Stearic acid 3.50

y Aspergullus mgcr 9642 Penieillium luteum 9644 f g l 2-88 2-88 Candidaalbicans 11ml exanetrio Propylene g y 68.00 6650 Trlcophytonmentagrophytes 9533 "molecular weight 6000.

""l-n ny divl- 15 The test procedure was as follows:

Twenty-four hour broth cultrues of the listed bacteria EXAMPLE 4 wereprepared in Tryptose Phosphate Broth. The molds Following the generalprocedure of Example 3, a formula based entirely on stearly alcohol forthe saturated monohydric alcohol was found to be suitable. Theingredients of this formula are shown below.

Formula G lngredients Concentration. wt.

Stearyl alcohol 30.0 Propylene glycol 70.0

l,2-pro ylcnt: diol EXAMPLE 5 Following the general procedure of Example3, the following satisfactory formulations can be ,prepared.

EXAMPLE 6 In this example, 0.25 gm. of 6a,9a-difluoro-llB-hydroxy-l601,17a-isopropylidenedioxy-21-acetoxypregna-l,4-diene-3,20-dione, was mixed with 100 gm. of Formula A,Example 1 to form a highly effective anti-inflammatory mixture. Thesteroid was .dissolved in 680 gm. of propylene glycol at 9095C. Thelatter then was mixed with a mixture of the other ingredients at 8085C.The mixture was cooled to room temperature with good agitation, mixedwith the remainder of the propylene glycol heated to C, allowed tosettle and deaerate overnight, gently mixed and filled into containers.

The mixture was tested and found to be mold and bacteria resistant asfollows. The test organisms used in the study were were grown inSabouraud Liquid Medium. Just prior to the performance of the assay, allthe test organisms were diluted 1:100 with the specific media asdiluent. 0.01 ml. of each diluted organism was intimately mixed with a15 ml. portion of the test material. Test samples inoculated with themixture of bacteria were incubated at 37C, and portions inoculated withthe mixture of molds were incubated at room temperature. At the end of48 hours contact and two weeks contact, samples were removed and platedout on appropriate media using the standard serial dilution technique.

The test compounds were found to be highly effective against bothbacteria and mold pooled cultures after two days and two weeks exposure.

The procedure, repeated with 6a,9a-difluoro- 11B,21-dihydroxy-16a,17aisopropylidenedioxypregna-1,4-diene-3,20-dione,yielded the same results.

EXAMPLE 7 The steroids used in Example 6 (0.25 gm.) are mixed with 1000gm. of each of Formulas B, C, D, E, F, G, H, l, J, K and L by thegeneral procedure described in Example 6, the steroid being dissolved inglycol solvent before being mixed with the other components. The productcompositions are mold and bacteria resistant when tested by theprocedure described in Example 6.

EXAMPLE 8 Each of 0.25, 0.5 and 1.0 gm. quantities of the followinganti-inflammatory steroids, when mixed with 1000 gm. of each of thevehicles described in Examples l-5, inclusive, are effective for topicaltreatment of inflammation:

9a-fluoro-l 1B,17a,21-trihydroxy-l 6/3- methylpregna- 1 ,4-diene-3,20-dione,

9a-fluoro-l 13,2l-dihydroxy-l6B-methyl-17avaleroxy-pregna- 1 ,4-diene-3,20-dione,

l7a,21-dihydroxypregn-4-ene-3,1 1,20-trione,

17a-hydroxy-2l-acetoxypregn-4-ene-3,1 1 ,20-trione,

601,9 a-difluoro-l 13-hydroxy-l6o1,1701- isopropylidenedioxy-Z l-acetoxypregna-l ,4-diene- 3,20-dione,

601-methyl-9o1-fluoro-l 13,1701-dihydroxypregna-l ,4- diene-3,20-dione.

601-fluoro-l 13,1701,2l-trihydroxypregna-l ,4-diene- 3,20-dione.

601-fluoro-l 13,2l-dihydroxy-l601,1701-isopropylidenedioxypregn-4-ene-3,20-dione,

601-fluoro-1 13,21-dihydroxy- 1 601,] 701- isopropylidenedioxypregna-l,4-diene-3.20-dione.

1 13,17o1-dihydroxy-21-acetoxypregn-4-ene-3,20- dione,

601methyl-l l3,1701,2l-trihydroxypregna-l ,4-diene- 3,20-dione,

6o1-methyl-1 13,17a-dihydroxy-2l-acetoxypregna- 1,4-diene-3 ,20-dione,

6o1-fluoro-1 13,l701,21-trihydroxy-l601- methylpregnal ,4-diene-3,20-dione,

a-fluoro-l 13,17a-dihydroxy-1601-methyl-2lacetoxypregna-l,4-diene-3,20-dione,

601-fluoro-1 13,l701-dihydroxy-16a-methyl-21- valeroxypregna- 1,4-diene-3,20-dione,

1 13,1 701,2 1 -trihydroxypregna-l ,4-diene-3,20-dione,

1 13,1701-dihydroxy-2l-acetoxypregna-l ,4-diene- 3,20-dione,

l 701,21-dihydroxypregna-1 ,4-diene-3,l 1,20-trione,

1701-hydroxy-2l-acetoxypregna-l ,4-diene-3 ,l 1,20- trione,

9a-fluoro-l 13,1601,l 701,2l-tetrahydroxypregna-l ,4- diene-3,20-dione,

901-fluoro-1 13,1601,l7o1-trihydroxy-2lacetoxypregna-l,4-diene-3,20-dione,

9o1-fluoro-1 13,2 l-dihydroxy-1601,l7o1-isopropylidenedioxypregna-1,4-diene-3 ,20-dione,

6o1-fluoro-901,l l3-dichloro-1601,1701- isopropylidenedioxy-2 1-hydroxypregna-l ,4-diene- 3,20-dione,

6a901-difluoro-l 13,2l-dihydroxy-l6a-methyl-1701-valeroxypregna-l,4-diene-3,20-dione, 601,901-difluorol13,1701,2l-trihydroxy-16o1-methylpregna-1,4-diene- 3,20-dione,

6a,701-difluoromethylene-1 l3,1701,21-trihydroxypregn-4-ene-3,20-dione,

601-fluoro-1 13,21-dihydroxy- 1601-methylpregna-l ,4- diene-3,20-dione,and

601,901-difluoro-l 13-hydroxy- 161:1,1 701- isopropylidenedioxy-Z l-chloropregna-l ,4-diene-3,20- dione.

The invention claimed is:

l. A substantially anhydrous pharmaceutical vehicle of cream-likeconsistency consisting essentially of a. from 20 to 35 parts by weightsaturated fatty alcohol having from 16 to 24 carbon atoms, b. from 55 to80 parts by weight of a glycol solvent selected from the groupconsisting of 1,2-

propylenediol. 1,3-propylenediol, dipropylene glycol, and mixturesthereof,

c. from O to 15 parts by weight of compatible plasticizer,

d. from 0 to 15 parts by weight of compatible coupling agent,

e. from 0 to 20 parts by weight of penetrant. and

f. from 0 to 3 weight percent water, the composition being substantiallyfree from petrolatum. mineral oil, monohydric fatty alcohols and fattyacids which are unsaturated, and monohydric alcohols. fatty acids andfatty amides which have less than 16 carbon atoms, said vehicle beingparticularly suitable for providing an occlusive film for releasingtopically active cortico-steroids, and for distributing medication overthe skin surface and maintaining it there until beneficial actionoccurs.

2. The vehicle of claim 1 wherein said vehicle includes c. from 2 to 10parts by weight of compatible plasticizer, and

d. a concentration of coupling agent sufficient to prevent visibleexudation of the glycol solvent from the composition after storage for48 hours at 45C,

e. and from 0 to 10 parts by weight penetrant.

3. The composition of claim 1 wherein the compatible plasticizer ispolyethylene glycol having a molecular weight of from above 800 up to20,000, hexanetriol, sorbitol, glycerol or mixtures thereof.

4. The composition of claim 1 wherein the compatible coupling agent isfatty acid having from 16 to 24 carbons, fatty amide having from 16 to24 carbons, fatty acid monoester with aliphatic alcohols or mixturesthereof.

5. The vehicle of claim 1 wherein said glycol solvent is propyleneglycol, said propylene glycol being admixed with a polyethylene glycolwhich is liquid at room temperature.

6. A vehicle of claim 5 wherein said propylene glycol is1,2-propylenediol.

7. A vehicle of claim 5 wherein said polyethylene glycol has an averagemolecular weight of about 400.

8. A vehicle of claim 5 wherein said propylene glycol is1,2-propylenediol and said polyethylene glycol has an average molecularweight of about 400.

9. The vehicle of claim 1 wherein the glycol solvent UNITED STATESPATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,888,995 DATED July18, 1975 |NVENTOR(S) Martin Katz et al It is certified that errorappears in the above-identified patent and that said Letters Patent arehereby corrected as shown below:

Column 9, line 39, in the heading of the Table on Example 5,

change "II" to H Column 11, line 40,

llB,l7oc,2l-trihydroxy-l6or-methylpregna-l,4-diene-3,20-dione,

should be read as a separate listing. change "composition" to vehiclechange "composition" to vehicle Column 12, line 26,

Column 12, line 30, Column 12, line 50,

change "stearly" to stearyl '[SEAL] Attest:

RUTH C. MASON Arresting Officer Signed and Bealcd this ninth D 3y OfDecember 1 9 75

1. SUBSTANTIALLY ANHYDROUS PHARMACEUTICAL VEHICLE OF CREAM-LIKECONSISTENCY CONSISTING ESSENTIALLY OF A. FROM 20 TO 35 PARTS BY WEIGHTSATURATED FATTY ALCOHOL HAVING FROM 16 TO 24 CARBON ATOMS B. FROM 55 TO80 PARTS BY WEIGHT OF A GLYCOL SOLVENT SELECTED FROM THE GROUPCONSISTING OF 1,2-PROPYLENEDIOL, 1,3PROPYLENEDIOL, DIPROPYLENE GLYCOL,AND MIXTURES THEREOF, C. FROM 0 TO 15 PARTS BY WEIGHT OF COMPATIBLEPLASTICIZER, D. FROM 0 TO 15 PARTS BY WEIGHT OF COMPATIBLE COUPLINGAGENT, E. FROM 0 TO 20 PARTS BY WEIGHT OF PENETRANT, AND F. FROM 0 TO 3WEIGHT PERCENT WATER, THE COMPOSITION BEING SUBSTANTIALLY FREE FROMPETROLATUM, MINERAL OIL, MONOHYDRIC FATTY ALCOHOLS AND FATTY ACIDS WHICHARE UNSATURATED, AND MONOHYDRIC ALCOHOLS, FATTY ACIDS AND FATTY AMIDESWHICH HAVE LESS THAN 16 CARBON ATOMS, SAID VEHICLE BEING PARTICULARLYSUITABLE FOR PROVIDING AN OCCLUSIVE FILM FOR RELEASING TOPICALLY ACTIVECORTICO-STERIODS, AND FOR DISTRIBUTING MEDICATION OVER THE SKIN SURFACEAND MAINTAINNG IT THERE UNTIL BENEFICAL ACTION OCCURS.
 2. The vehicle ofclaim 1 wherein said vehicle includes c. from 2 to 10 parts by weight ofcompatible plasticizer, and d. a concentration of coupling agentsufficient to prevent visible exudation of the glycol solvent from thecomposition after storage for 48 hours at 45*C, e. and from 0 to 10parts by weight penetrant.
 3. The composition of claim 1 wherein thecompatible plasticizer is polyethylene glycol having a molecular weightof from above 800 up to 20,000, hexanetriol, sorbitol, glycerol ormixtures thereof.
 4. The composition of claim 1 wherein the compatiblecoupling agent is fatty acid having from 16 to 24 carbons, fatty amidehaving from 16 to 24 carbons, fatty acid monoester with aliphaticalcohols or mixtures thereof.
 5. The vehicle of claim 1 wherein saidglycol solvent is propylene glycol, said propylene glycol being admixedwith a polyethylene glycol which is liquid at room temperature.
 6. Avehicle of claim 5 wherein said propylene glycol is 1,2-propylenediol.7. A vehicle of claim 5 wherein said polyethylene glycol has an averagemolecular weight of about
 400. 8. A vehicle of claim 5 wherein saidpropylene glycol is 1,2-propylenediol and said polyethylene glycol hasan average molecular weight of about
 400. 9. The vehicle of claim 1wherein the glycol solvent is 1,2-propylenediol.
 10. The vehicle ofclaim 1 wherein said vehicle contains about 30 parts by weight stearlyalcohol.
 11. The vehicle of claim 1 wherein said vehicle contains about30 parts by weight stearly alcohol, 5 parts by weight polyethyleneglycol 6000, 5 parts by weight 1,2,6-hexanetriol and about 60 parts byweight 1,2-propylenediol.